The clinical treatment of schizophrenia has long been defined by the dopamine hypothesis of schizophrenia, which holds that schizophrenia is a result of hyperactivity of dopaminergic neurotransmission, particularly in limbic brain structures such as nucleus accumbens (the mesolimbic dopamine system). Indeed, the positive symptoms of schizophrenia (hallucinations, delusions, thought disorder) are successfully treated with neuroleptics, which block dopamine receptors. However, such treatment is accompanied by the production of movement disorders or dyskinesias (extrapyramidal side effects), due to the blockade of nigrostriatal dopamine receptors. In addition, neuroleptics do not treat the negative symptoms of schizophrenia (social withdrawal, anhedonia, poverty of speech) which are related to a relative hypoactivity of neurotransmission in the mesocortical dopamine system and which respond to treatment by dopamine agonists.
Efforts to induce antipsychotic activity with dopamine autoreceptor agonists have been successful (Corsini et al., Adv. Biochem. Psychopharmacol. 16, 645-648, 1977; Tamminga et al., Psychiatry 398-402, 1986). A method for determining intrinsic activity at the dopamine D2 receptor was recently published [Lahti et al., Mol. Pharm. 42, 432-438, (1993)]. As reported, intrinsic activity is predicted using the ratio of the xe2x80x9clow-affinity agonistxe2x80x9d (LowAg) state of the receptor and the xe2x80x9chigh-affinity agonistxe2x80x9d (HighAg) state of the receptor, i.e. LowAg/HighAg. These ratios correlate with agonist, partial agonist, and antagonist activities for a given compound, which activities characterize a compound""s ability to elicite an antipsychotic effect.
Dopamine autoreceptor agonists produce a functional antagonism of dopaminergic neurotransmission by the reduction of neuronal firing and the inhibition of dopamine synthesis and release. Since dopamine autoreceptor agonists are partial agonists at postsynaptic dopamine receptors, they provide a residual level of stimulation sufficient to prevent the production of dyskinesias. Indeed, partial agonists are capable of functioning as either agonists or antagonists depending on the level of dopaminergic stimulation in a given tissue or brain region, and would therefore be expected to have efficacy versus both positive and negative symptoms of schizophrenia. Thus, novel dopamine partial agonists are of great interest for the treatment of schizophrenia and related disorders.
The present invention discloses compounds represented by Formula (I) which are useful antipsychotic agents: 
wherein:
X is H, CF3, alkyl of 1 to 10 carbon atoms, phenyl optionally substituted with one to three substituents independently selected from alkyl of 1 to 10 carbon atoms, xe2x80x94O-alkyl of 1 to 10 carbon atoms, xe2x80x94S-alkyl of 1 to 10 carbon atoms, xe2x80x94CN, xe2x80x94NO2, and halogen; or phenylalkyl of 7 to 9 carbon atoms where the phenyl ring is optionally substituted with one to three substituents independently selected from hydroxy, amino, halogen, alkyl of 1 to 10 carbon atoms, cyano, nitro, alkylamino of 1 to 10 carbon atoms, and dialkylamino of 1 to 10 carbon atoms;
R1 is H, alkyl of 1 to 10 carbon atoms, xe2x80x94CH2-cycloalkyl of 3 to 10 carbon atoms,
xe2x80x94CH2-bicycloalkyl of 7 to 10 carbon atoms, 
R is: 
m is an integer of 0 to 4;
R2 is H or alkyl of 1 to 10 carbon atoms;
R3 is H, halogen, alkyl of 1 to 10 carbon atoms, xe2x80x94O-alkyl of 1 to 10 carbon atoms or hydroxy;
Z is O, S, or xe2x80x94CH2xe2x80x94;
or R1 and R2 when taken together with the nitrogen atom to which they are attached form a moiety of the formula: 
n is an integer of 1 or 2;
R7 and R8 are independently selected from H, halogen, alkyl of 1 to 10 carbon atoms, xe2x80x94O-alkyl of 1 to 10 carbon atoms or hydroxy;
R4 and R5 are independently hydrogen, alkyl of 1 to 10 carbon atoms, xe2x80x94O-alkyl of 1 to 10 carbon atoms, xe2x80x94S-alkyl of 1 to 10 carbon atoms, xe2x80x94CN, xe2x80x94NO2, or halogen; or a pharmaceutically acceptable salt thereof.
Preferred are compounds of Formula (I) wherein R1 is xe2x80x94(CH2)mZxe2x80x94R where m is 0, Z is xe2x80x94CH2xe2x80x94 and R is selected from the group consisting of: 
and 
and R1, R2, R3, R7, X, Y and n are hereinbefore defined.
A particularly preferred compound of this invention according to general Formula (I) is benzyl-(2-trifluoromethyl-1,6,7,8-tetrahydro-9-oxa-1,3-diazacyclo-penta[a]naphthalen-8-ylmethyl)-amine and pharmaceutical salts thereof.
In particular, the present invention also provides methods of treating diseases of brain dopamine dysregulation such as schizophrenia, Parkinson""s disease, hyperprolactinemia, depression. Because compounds of the present invention are partial agonists at the postsynaptic dopamine D2 receptor they are also useful in the treatment of alcohol and drug addiction in warm-blooded animals, in need thereof. Thus, an effective amount of compound of the present invention is administered to a warm-blooded animal, preferably mammal, most preferably human.
For the compounds defined above and referred to herein, unless otherwise noted; halogen, or halo as used herein means chloro, fluoro, bromo and iodo.
Alkyl as used herein means a branched or straight chain having from 1 to 10 carbon atoms and more preferably from 1 to 6 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
Cycloalkyl as used herein means a saturated ring having 3 to 10 carbon atoms and more preferably from 3 to 6 carbon atoms. Exemplary cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term bicycloalkyl means fused saturated bicyclic rings having 7 to 10 carbon atoms. Exemplary bicycloalkyl rings include bicyclo[3.3.1]nonane, bicyclo[3.3.0]octane, bicycloheptane[2.2.1], bicyclooctane[3.2.1], bicyclononane-[4.3.0], and bicyclodecane[4.4.0].
Phenyl as used herein refers to a 6-membered aromatic ring.
The range of carbon atoms defines the number of carbons in the carbon backbone and does not include carbon atoms occurring in substituent groups.
It is understood by those practicing the art that the definition of compounds of Formula (I) when R1, R2, and R3 contain asymmetric carbons, encompass all possible stereoisomers, mixtures and regioisomers thereof which possess the activity discussed below. Such regioisomers may be obtained pure by standard separation methods known to those skilled in the art. In particular, the definition. encompasses any optical isomers and diastereomers as well as the racemic and resolved enantiomercially pure R and S stereoisomers as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof, which possess the activity discussed below. Optical isomers may be obtained in pure form by standard separation techniques or enantiomer specific synthesis. It is understood that this invention encompasses all crystalline forms of compounds of Formula (I). The pharmaceutically acceptable salts of the basic compounds of this invention are those derived from such organic and inorganic acids as: lactic, citric, acetic, tartaric, fumaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic and similarly known acceptable acids.
The present invention further provides a pharmaceutical composition which comprises a compound of Formula (I) of this invention in combination or association with a pharmaceutically acceptable carrier. In particular, the present invention provides a pharmaceutical composition which comprises an effective amount of a compound of this invention and one or more pharmaceutically acceptable carriers.
Compounds of Formula I are synthesized as described in Scheme I from substituted ethyl 7-hydroxy-8-nitro-4-oxochromen-2-carboxylate 1 where R3 is hereinbefore defined by reaction with p-toluenesulfonyl chloride to give tosylate 2. Reaction of tosylate 2 with substituted benzylamine 3 where R6 is hydrogen, alkyl of 1 to 10 carbon atoms, xe2x80x94O-alkyl of 1 to 10 carbon atoms, halogen or xe2x80x94NO2 at 100 to 180xc2x0 C. in o-dichlorobenzene affords ethyl-7-substituted benzylamino-8-nitro-4-oxo-4H-chromene-2-carboxylate 4 where R3 and R6 are hereinbefore defined, followed by hydrogenation in the presence of palladium-on-carbon to give ethyl substituted-7,8-diamino-chroman-2-carboxylate 5. Heating ethyl substituted-7,8-diamino-chroman-2-carboxylate 5 with an appropriately substituted acid such as trifluoroacetic acid (where R8 is alkyll of 1-6 carbon atoms) affords ethyl substituted 2-trifluoromethyl-3,6,7,8-tetrahydro-9-oxa-1,3-diaza-cyclopenta[a]-naphthalene-8-carboxylate 6 or the like where R3 is hereinbefore defined, which is followed by reduction in the presence of lithium borohydride to give alcohol 7 where R3 is hereinbefore defined. Further reaction of alcohol 7 with p-toluenesulfonyl chloride in pyridine affords tosylate 8 where R3 is hereinbefore defined and which is further reacted with disubstituted benzylamine 9 where R4 and R5 are hereinbefore defined, in dimethylsulfoxide to give substituted benzyl-(2-trifluoromethyl-1,6,7,8-tetrahydro-9-oxa-1,3-diaza-cyclopenta[a]-naphthalen-8-ylmethyl)amine 10 where R3, R4 and R5 are hereinbefore defined. 
The compounds of the present invention can be readily prepared according to hereinbefore described reaction schemes and hereinafter described examples or modifications thereof using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformation being effected. It is understood by those skilled in the art of organic synthesis that the various functionalities present on the molecule must be consistent with the chemical transformations proposed. This may necessitate judgement as to the order of synthetic steps, protecting groups, if required, and deprotection conditions. Substituents on the starting materials may be incompatible with some of the reaction conditions. Such restrictions to the substituents which are compatible with the reaction conditions will be apparent to one skilled in the art. Some of the compounds of the hereinbefore described schemes have centers of asymmetry. The compounds may, therefore, exist in at least two and often more stereoisomeric forms.
Affinity for the dopamine autoreceptor was established by a modification of the standard experimental test procedure of Seemen and Schaus, European Journal of Pharmacology 203: 105-109, 1991, wherein homogenized rat striatal brain tissue is incubated with [3H]-quinpirole (Quin.) at various concentrations of test compound, filtered, washed and counted in a Betaplate scintillation counter.
High affinity for the dopamine D2 receptor was established by the standard experimental test procedure of Fields, et al., Brain Res., 136, 5789 (1977) and Yamamura et al., ed., Neurotransmitter Receptor Binding, Chapter 9, page 171, Raven Press, N.Y. (1978) wherein homogenized limbic brain tissue is incubated with [3H]-spiperidone at various concentrations of test compound, filtered washed, and shaken with Hydrofluor scintillation cocktail (National Diagnostics) and counted in a Packard 460 CD scintillation counter.
The results of the tests with compounds representative of this invention are given below.
Thus, compounds of the present invention are dopamine autoreceptor agonists which serve to modulate the synthesis and release of the neurotransmitter dopamine. The compounds are useful for the treatment of dysregulation disorders of the dopaminergic system, such as schizophrenia, schizoaffective disorders, bipolar disorders, L-DOPA induced psychoses and dipkinesias, Parkinson""s disease, hyperprolactinemia, depression, and Tourette""s syndrome. Compounds of the present invention are also partial agonists at the postsynaptic dopamine D2 receptor and are accordingly useful in the treatment of alcohol and drug addiction, such as cocaine and analagous drugs.
The compounds of this invention may be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers. Applicable solid carriers for pharmaceutical compositions containing the compounds of this invention can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water particularly containing additives as above e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution, alcohols (including monohydric alcohols and polyhydric alcohols e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
Preferably, the pharmaceutical composition is in unit dosage form, e.g., as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient: the unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
The dosage to be used in the treatment of a specific condition must be subjectively determined by the attending physician. The variables involved include the specific psychosis and the size, age and response pattern of the patient. The treatment of substance abuse follows the same method of subjective drug administration under the guidance of the attending physician. Based upon the potency of the compounds of this invention as reported above, the human dose lies between about 5 to about 100 mg/day. As is conventional, the treatment is begun with the lower dose with gradual increase at the rate of about 5 mg/day until the desired response pattern is achieved. The optimum human dosage will lie in the range of about 15 mg/day to about 75 mg/day.
The most preferred compounds of the invention are any or all of those specifically set forth in these examples. These compounds are not, however, to be construed as forming the only genus that is considered as the invention, and any combination of the compounds or their moieties may itself form a genus. The following examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.